Randomized, Double-Blind Study of Timolol (A Nonselective Beta-Adrenergic Blocker) vs Placebo to Prevent Complications of Hepatic Portal Hypertension in Patients With Cirrhosis
Overview
- Phase
- Phase 3
- Status
- Completed
- Enrollment
- 213
- Locations
- 5
- Primary Endpoint
- Varices
Overview
Brief Summary
The purpose of this study is to learn whether timolol is useful in preventing or delaying the appearance of gastroesophageal varices, a complication that may develop in the future as a consequence of liver disease. Cirrhosis causes an increased resistance of blood flowing through the liver. This leads to an increased pressure in the portal vein (the vein that takes blood to your liver). High portal pressure is responsible for the appearance of complications of chronic liver disease such as varices and variceal bleeding (bleeding from veins in your esophagus). Timolol belongs to a group of medications called beta-blockers. Beta-blockers decrease high portal pressure and previous studies have shown that beta-blocker pills are useful in preventing bleeding from varices in patients who already have varices. A more desirable effect would be if these pills could prevent not only bleeding from varices but the appearance of varices (and therefore of bleeding).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Liver biopsy compatible with cirrhosis.
- •Absence of gastroesophageal varices.
- •An increased hepatic venous pressure gradient (HVPG) (6mmHg).
- •Age over 18 and below 76 years.
- •Informed, written consent.
- •Absence of exclusion criteria.
Exclusion Criteria
- •Presence of ascites that requires specific treatment (diuretics, paracentesis, peritoneo-venous shunt, etc).
- •Proven hepatocellular carcinoma by radiological or histological criteria.
- •Splenic or portal vein thrombosis by Doppler-ultrasound.
- •Presence of any concurrent disease that is expected to decrease life expectancy to less than one year.
- •Patients taking diuretics, beta-blockers, clonidine, prazosin, nitrates, molsidomine and any drug which may have an effect on splanchnic hemodynamics/portal pressure.
- •Patients participating in other pharmacological randomized clinical trials.
- •Patients with primary biliary cirrhosis and primary sclerosing cholangitis will also be excluded since these entities have a slower progression of the disease, are usually enrolled in other clinical trials and are transplanted at an earlier stage.
- •Contraindications to beta-blockers: asthma, COPD with positive broncoconstrictive test, heart failure, A-V block, aortic valve stenosis, organic psychosis, insulin-dependent diabetes, hypersensitivity to beta-blockers.
- •Women who are pregnant, nursing or of childbearing potential and who are not using oral or mechanical contraception.
Arms & Interventions
Timolol Maleate
Dose titrated from 5 mg per day to up to 80 mg per day depending on heart rate
Intervention: Timolol Maleate (Drug)
Placebo
Timelol placebo
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Varices
Time Frame: 6 years
Development of varices
Secondary Outcomes
No secondary outcomes reported